4-(beta-aminopropionylamino)-antipyrines



United States Patent ()fiiice 3,320,253 Patented May 16, 1967 3,329,253 4-(B-AMENQPROPIONYLAMINO). ANTHPYRINES Herbert Miihle, Basel, Switzerland, assignor to Chemiscile Fabrilr Schweizerhall, Basel, Switzerland, a Swiss com- P y No Drawing. Filed Dec. 2, 1964, Ser. No. 415,454 Claims priority, application Switzerland, Dec. 3, 1963, 14,777/63 15 Claims. (Cl. 260-2472) The present invention relates to a process for preparing new 4-amino-antipyrine derivatives having valuable physiological properties and corresponding to the general formula wherein R may denote hydrogen or an alkyl radical and R may denote the radical of a saturated or unsaturated, substituted or unsubstituted heterocyclic amine, aromatic amine or araliphatic amine, linked by means of a nitrogen atom, such as a nitrogenous aromatic n being equal to 0, 1 or 2, or the radical of an unsubstituted or substituted alkylene imine wherein X means chlorine or bromine, if desired with a saturated or unsaturated, substituted or unsubstituted heterocyclic amine, an aromatic amine or an araliphatic amine.

The reaction is preferably performed in an inert organic solvent, e.g., chloroform, benzene, dioxane and the like, at elevated temperature. If the reaction is performed in stoichiometric quantity ratios, an inorganic or tertiary organic base, such as alkali carbonate, triethylamine and the like, is advantageously added to the reaction mixture.

The invention will be described in greater detail with reference to the following examples, but is not intended to be restricted thereto.

Example I 9 g. of ,B-bromopropionic acid chloride were added in portions while stirring to a solution of 10- g. of 4-arnin0- antipyrine and 5.5 g. of triethylamine in 100 ml. of absolute benzene. The solution was stirred for 15 minutes at normal temperature and then heated for a further 10 minutes on a water-bath. The resulting precipitate was filtered oil, stirred with water and recrystallized from alcohol. 9 g. (78% of the theory) of 4-(fi-bromopropionylamino)-antipyrine having a melting point of 178- 180 were obtained.

Example 2 2.6 of piperidine were added to a solution of 5 g. of 4-(fi-bromopropionylamino)-antipyrine in 60 ml. of dioxane and the solution was refluxed for 3 hours. After cooling, one separated off from the precipitated piperidine-HBr and concentrated. The residue was dissolved in absolute benzene and filtered. After the addition of petroleum ether, crystals having a melting point of 143- 146 formed. After recrystallizing from benzene-petroleum ether, 4 g. of the theory) of 4-(fi-piperidinopropionylamino)-antipyrine having a melting point of 149-150 were obtained.

Example 3 10 g. of 4-(B-bromopropionylamino)-antipyrine were dissolved in ml. of absolute dioxane, diluted with 6.8 g. of 4-methylpiperidine and refluxed for 3 hours. After cooling, one filtered off from precipitated 4-methylpiperidine-HBr and concentrated. The residue was dissolved in methylene chloride and washed twice with a small amount of water. The methylene chloride solution dried with sodium sulfate was concentrated and the residue crystallized from benzene-petroleum ether. After recrystallizing from benzene-petroleum ether, 7.8 g. (74% of the theory) of 4-[fi-(4-methylpiperidino) propionylamino]-antipyrine having a melting point of 163 were obtained.

Example 4 10 g. of 4-(,B-bromopropionylamino)-antipyrine were dissolved in ml. of absolute dioxane, diluted with 8.6 g. of 4-phenylpiperidine and refluxed for 3 hours. One then concentrated, dissolved the residue in methylene chloride and washed three times with water. To crystallize, the methylene chloride solution dried with sodium sulfate was concentrated and diluted with petroleum ether. 9.5 g. of 4-[fi-(4-phenylpiperidino)-propionylamino] antipyrine having a melting point of -172 were obtained. This compound can also be converted into salts, e.g., hydrochloride or salicylate and the like.

Melting point of the hydrochloride: 263-266 (alcohol-ether).

3 Example 5 Further examples of compounds obtainable according to the invention and having the general formula are to be found in the following table:

Example R1 R2 Sum Formula M.P.,

6 H- N- C1gH24N4Oz... 160

7 H- N- C2DH23N40:.-- 126 8 H 6 N- C1sH24N4O:. 175

9 H- N- CZOHHNAOZ. 148

10 H- Q-NH- C2oH22N4O2- 164 11 /CH N- C22Hs2N402. 122

12 /CH- CH5 N C23H34N402 13 H )CHzCHa C2l 3DN-l02. 1G1

salicylate CzsHsaNaOs. 100

14 H --N CH2CH2CH3 C22H32N4Oz-.-

salioylete C2gH33N405- 130 r: e 15 H (|3H CzzHszNqOz.-.

16 CH3 --N CHzCH.-, C22Ha2N402..- 100 P 17 CH3 O(IJH C2aHa4N402 83 18 CH: N Cz0H2gN402 salicylate C 20H34N405. 92

Experiments which have been performed with the compounds of the invention have shown that these compounds have analgetic, antipyretic and especially marked antiphlogistic properties with comparatively low toxicity. The compounds of the invention can be used as such or in the form of their water-soluble salts, such as hydrochlorides, tartrates and salicylates. For example, 4-[5- (4-methylpiperidino)-propionylamino] antipyrine (I) has a better antiphlogistic effect in animal experiments than phenylbutazone (II), as the following comparison shows:

6 consisting of H and 'alkyl of 1 to 3 carbon atoms, and R is a member selected from the group consisting of piperidino, alkylpiperidino wherein the alkyl is alkyl of 1 to 3 carbon atoms, phenylpiperidino, pyrrolidino, mor- The determination of the an-tiphlogistic effect was performed on the paw of the rat. To cause the oedema, 0.1 ml. of a emulsion of hens protein, dextrane in 6% solution or serotonine hydrogen oxalate as a 0.0025% aqueous solution was injected subplantar into the right hindpaw of the animals. The measurement of the paw volume was performed plethysmographioally before and 1 and 2 hours after administering the phlogistic agent. Each measurement was performed 3-4 times and the average calculated from the result.

The DL is in the case of the mouse 328 mg/kg. intraperitoneally and 109 mg./kg. intravenously and in the case of the rat is 4750 mg/kg. per os. Pathologicalanatomical tests were also favourable. Thus, no changes in the blood picture of the animals were noticed after administration to rats for 8 months.

In cases of primary chronic arthritis in humans, a decline of marked inflammation was seen after administration of 3 to 4 pills during about 5 to 10 days.

What I claim is:

1. A member selected from the group consisting of compounds of the formula and the pharmaceutically acceptable salts thereof with acids, wherein R is a member selected from the group pholino, hexamethyleneimino and 4-phenyl-1,2,3,6-tetrahydropyridino.

2. 4 ,B-bromopropionylamino -antipyrine.

3. 4-(fi-piperidino-propionylamino)-antipyrene.

4. 4 [,6 (4 phenylpiperidino propionylamino]- antipyrine.

5. 4 [6 (4 methylp'iperidino) propionylamino]- antipyrine.

6. 4 [B (4 phenyl 1:2:3z6 tetrahydropyridino)- propionylamino] -antipyrine.

7. 4- fi-pyrrolidino-propionylamino) -antipyrine.

8. 4 [[3 (2 methylpiperidino) propionylamino1- antipyrine.

9. 4-(,8-morp-holino-propionylamino)-antipyrine.

1t 4 (,8 hexamethyleneimino propionylamino)- antipyrine.

1 1. 4 [3-anilino-propionylamino -antipyrine.

12. 4 (N isopropyl N ,8 piper'idino ethylcarbonylamino -antipyrine.

13. 4 (N isopropyl N ,8 4 methylpiperidinoethyl-carbonylamino) -antipyrine.

14. 4 [B (4 alkylpiperidino) propionylaminoJ- antipyrine, alkyl being alkyl of 1 to 3 carbon atoms.

15. 4 (N alkyl N {3 4 alkylpiperidino ethylcarbonylamino)-antipyrine each alkyl being alkyl of 1 to 3 carbon atoms.

References Cited by the Examiner UNITED STATES PATENTS 2,912,460 11/1959 Ehrhart et a1, 260-562 ALEX MAZEL, Primary Examiner. JOSE TOVAR, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 